What is CHARGE Syndrome?
CHARGE syndrome is a rare genetic disorder that usually gets diagnosed early in life as it causes many physical and developmental issues. It was initially called Hall-Hittner syndrome, as these two scientists first independently reported its features. However, Pagon, another scientist, described the main characteristics of this disorder: coloboma (an eye defect), choanal atresia (a nose defect), heart issues, abnormal genital development, growth retardation, and ear abnormalities. He then gave it the name “CHARGE syndrome.”
The diagnosis now follows established criteria highlighting three specific abnormalities: coloboma, choanal atresia, and abnormal semicircular canals in the ear. Other factors include distinctive facial features, cleft lip or palate, a connection between the windpipe and esophagus, arm and leg abnormalities, and rarely, immune system issues.
The syndrome is due to mutations in a specific gene, CHD7, located on chromosome 8. This mutation results in several physical structural and functional problems, including hearing and vision loss, heart defects, and digestive system issues. Notably, digestive problems deeply impact a person’s life, leading to increased illness and death rates.
What Causes CHARGE Syndrome?
The most common cause of CHARGE syndrome is changes or mutations in the CHD7 gene. In some rare circumstances, this condition can be passed on from parent to child, a trait known as autosomal dominant inheritance. But most of the times, these changes in the CHD7 gene happen on their own, without being passed down from parents; these are called de novo mutations. This means that over 90% of the kids who fit the clinical symptoms of CHARGE syndrome have these newly-happened changes in the CHD7 gene.
So just to give you a gist, the CHD7 gene’s job is to manage the production of a special protein that plays a huge role in growth processes through organizing chromatin, a substance inside a cell’s nucleus. Mutations in the CHD7 gene produce a shortened, nonfunctional version of this protein. This ends up disrupting normal gene regulation and disrupts the development of neural crest cells, a type of early developing cell. The consequence of this interruption is the characteristic wide-ranging signs and symptoms of CHARGE syndrome that usually present during the embryonic stage – when a baby is still growing inside the womb.
Risk Factors and Frequency for CHARGE Syndrome
CHARGE syndrome is a rare condition that is present at birth and affects around 1 in every 10,000 births. This condition does not favor any gender, meaning both boys and girls have equal chances of being affected. Most of the time, it happens spontaneously and is not passed down through families, although fathers tend to be a bit older on average. In 2010, a study was carried out on 379 patients diagnosed with CHARGE syndrome. This study included a mutation test for CHD7, a gene linked to this condition. It was found that 67% of the cases in the study were due to this mutation. It’s also worth noting that this condition doesn’t often reoccur, with a low recurrence rate of 1%.
- CHARGE syndrome affects around 1 in 10,000 births.
- It is not linked to sex – both boys and girls can have it.
- Most cases occur randomly and are not inherited.
- The average age of fathers tends to be a bit higher.
- A 2010 study identified a CHD7 mutation in 67% of CHARGE syndrome cases.
- It very rarely reoccurs, with a recurrence rate of just 1%.
Signs and Symptoms of CHARGE Syndrome
CHARGE syndrome is a complex disorder that includes a variety of symptoms. These symptoms can include eye abnormalities such as coloboma, heart defects, issues with the back part of the nasal passage (choanal atresia), slow growth, genital abnormalities, ear anomalies, and hearing loss. It’s also common for individuals with CHARGE syndrome to experience hypoplasia of the semicircular canals leading to a lack of reflexes linked to balance.
Other related issues can include abnormal eye conditions, complete or partial blockage of the nasal passage, and cranial nerve abnormalities leading to a loss of smell, facial paralysis (either on one or both sides), hearing problems, and difficulty swallowing. CHARGE syndrome can also cause an abnormal ear shape, undescended testicles, hormonal imbalances in both males and females, developmental delays, cleft lip or palate, abnormal connections between the windpipe and the esophagus (tracheoesophageal fistula), and certain behavior issues similar to autism.
- Hypoplasia of the semicircular canals with corresponding lack of balance reflexes
- Abnormalities of the eyes (coloboma)
- Nasal passage issues (choanal atresia)
- Cranial nerve abnormalities, such as loss of smell, facial paralysis
- Abnormal ear shape
- Undescended testicles in males
- Hormonal imbalances
- Developmental delays
- Cleft lip or palate
- Tracheoesophageal fistula
- Autistic-like behavior
The presence of CHARGE syndrome is typically indicated by a detailed review of the individual’s medical history, which includes prenatal, neonatal, and childhood health issues. The prenatal health is particularly monitored when there’s slow fetal growth, intrauterine growth restrictions, cleft lip or palate, or heart defects detected in the womb.
Newborns with CHARGE syndrome often have numerous severe medical conditions. They might be smaller than normal for their gestational age, have trouble passing a nasal feeding tube due to nasal passage blockages, show abnormal facial features, and experience respiratory distress. Children with CHARGE syndrome often struggle with feeding, which can be a major source of health problems throughout all age groups.
Testing for CHARGE Syndrome
CHARGE syndrome diagnosis is initially based on certain clinical findings and temporal bone imaging. The disease is connected to one specific gene, named CHD7, which produces a DNA binding protein. Testing this gene generally identifies damaging variants in patients who exhibit the typical CHARGE syndrome characteristics. These characteristics can be major or minor, with the main ones often referred to as the 4C’s. They include colobema (defects in the eye), cranial nerve abnormalities, choanal atresia (blockage of the nasal passages), and a typical CHARGE ear. Minor characteristics include heart defects, cleft lip or palate, genitals abnormalities, low muscle tone (hypotonia), kidney abnormalities, esophageal atresia (disorder of the digestive system), poor growth, typical CHARGE face, and typical CHARGE hand.
In general, about 65% to 70% of people that show fewer significant features or have the typical CHARGE syndrome, have harmful variants detected through CHD7 analysis. The process of diagnosis usually includes clinical presentation, laboratory tests, genetic analysis, and imaging assessments:
Clinical diagnosis includes a combination of major and minor diagnostic characteristics.
Lab analysis includes getting your bloodwork, like a complete blood count (CBC), serum electrolytes, renal function test, luteinizing hormone-releasing hormone, Human chorionic gonadotropin (hCG), blood urea nitrogen (BUN), creatinine, growth hormone levels, and immunological studies.
Genetic analysis is particularly recommended for family cases, generally conducted pre-birth via amniocentesis or villus sampling between 10 to 12 and 18 to 20 weeks of pregnancy.
Imaging studies could involve a skeletal survey, abdominal ultrasound, a barium swallow, echocardiography (heart ultrasound), a chest x-ray, cranial ultrasound for newborns, and head CT scans or MRIs.
Treatment Options for CHARGE Syndrome
Patients with CHARGE syndrome need specialized medical and surgical management plans. The exact plan depends on when the syndrome is diagnosed, the specific features it includes, and its severity. The most dangerous aspects are usually heart defects and blocked nasal passages, both of which can restrict the oxygen supply in newborn babies.
Because of this risk, every patient suspected of having CHARGE syndrome should see a heart specialist. If it turns out that the newborn’s primary source of blood flow to the lungs is a small vessel designed to close shortly after birth, they should be given a medication called prostaglandin to keep it open.
Sometimes, a tracheostomy, which is a hole made in the neck to assist with breathing, may be necessary to manage long-term difficulties with the airways. Aspiration, or the inhalation of food or liquid particles into the lungs, and acid reflux disease may also need to be addressed. Many children with CHARGE syndrome suffer from feeding difficulties and need medically inserted feeding tubes.
As inserting a breathing tube can be particularly challenging in children with CHARGE syndrome, any planned surgeries should involve a specialist pediatric ear, nose, and throat doctor or an anesthesiologist. A facial nerve issue could lead to clouding of the cornea, which can be prevented with the use of artificial tears. Any hearing loss should be dealt with promptly, ideally with a hearing aid that is regularly updated to fit the child’s ear as they grow. There may be challenges with fitting the aid as the ear canals can be quite small at first, and there may not be enough support structure in the ear.
Some children with CHARGE syndrome have a cochlear implant, which is a small electronic device that can partially restore hearing. If this is done, it’s important to teach them sign language alongside speech therapy.
In terms of hormonal issues, male patients with CHARGE syndrome may need sex steroid therapy for the development of the testes and the penis. Testosterone is given for delayed puberty in teenage boys. Girls may need hormone replacement therapy at puberty if necessary. This therapy can also prevent bone weakening.
Any occurrence or suspicion of a cleft palate, even when it’s hidden under the lining of the roof of the mouth, should be addressed with surgery at an appropriate age, ideally involving a specialist facial surgeon. Any nerve-related issues identified with a physical checkup should be evaluated to ensure facial nerve integrity.
Regular discussions with a genetic counselor or geneticist are also recommended for ongoing support and guidance.
What else can CHARGE Syndrome be?
- 2 deletion syndrome
- Condition causing a defect in the eye called coloboma
- Condition causing a blockage of the nasal passageway known as choanal atresia
- Condition causing isolated heart abnormalities from birth
- Cat-eye syndrome, a rare genetic disorder
- Joubert spectrum, a group of disorders affecting multiple body systems
- Kabuki syndrome, a rare condition that affects many parts of the body
- Holoprosencephaly spectrum disorders, conditions where the brain doesn’t divide properly
- Renal coloboma syndrome, associated with kidney and eye abnormalities
- VATER/VACTERL association, a non-random association of birth defects
- Kalman syndrome, a hormonal disorder leading to absence or delay in puberty
- Smith-Lemli-Opitz syndrome, a developmental disorder
- DiGeorge syndrome, a disorder caused by a defective chromosome
What to expect with CHARGE Syndrome
Infants, particularly those with severe birth defects, are at a high risk of developing health complications. Consequently, these children experience poor health outcomes with a high rate of sickness and death. They are most vulnerable during their first year of life, likely to get infections, require frequent hospital visits, and even need complex surgeries such as heart surgery.
In later childhood and adulthood, death commonly results from infection, aspiration (breathing in a foreign substance), and sleep apnea (a disorder where breathing repeatedly stops and starts during sleep). Severe eye defects leading to poor vision, brain malformation, and a smaller than normal head size (microcephaly) also contribute to a poor prognosis or outlook.
Possible Complications When Diagnosed with CHARGE Syndrome
Some issues that individuals might encounter include:
- Difficulty swallowing
- Aspiration, or inhaling foreign objects into the airways
- Corneal ulceration, or having an open sore on the cornea (the clear front surface of the eye)
- Retinal detachment, which is a serious eye condition that occurs when the retina (located at the back of the eye) pulls away from its normal position
Preventing CHARGE Syndrome
Families of patients with CHARGE syndrome, a complex genetic disorder, should be guided on the various aspects of the problem and possible complications. Those who have a higher risk of having affected children should have access to genetic counseling. This helps them understand their choices for future pregnancies, which could include methods like early genetic testing before and during pregnancy.
Children with CHARGE syndrome are unique and their needs vary. Some might need full-time support and specially designed programs, while others may require minimal help. It’s crucial to understand why certain behavioral issues arise and teach the child more appropriate ways of communication and interaction.
As a child reaches 18 years old, it’s important that they transition from pediatricians to adult health care providers. The latter will handle the patients’ needs and health conditions in their later years.
